Testicular SIRT1 Loss Reveals an Aging-Like Proteomic Landscape and Precipitates Reproductive Deterioration

Advanced paternal age is associated with reduced male fertility and testicular dysfunction. Among the molecular regulators involved in aging, SIRT1, a NAD⁺-dependent deacetylase, plays a pivotal role in maintaining oxidative balance and cellular homeostasis. Although the age-associated decline in SIRT1 levels is well established, the extent to which this reduction underlies testicular dysfunction and the specific proteomic alterations linked to it remain to be elucidated.

This study aimed to determine whether testicular SIRT1 insufficiency contributes to testicular aging by promoting changes in the proteomic landscape and impairing male reproductive function.

We employed a Sirt1⁺/^- mouse model that mimics the partial SIRT1 decline observed during aging. Comparative analyses were conducted across wild type, aged wild type, and Sirt1⁺/^- males. We assessed reproductive performance, testicular histology, sperm quality, and embryo development. In parallel, we performed proteomic profiling of testicular tissue to identify molecular pathways affected by aging and SIRT1 insufficiency.

Sirt1⁺/^- males exhibited marked reproductive impairments, including reduced fertility, compromised embryo development, sperm morphological abnormalities, and increased testicular tubule degeneration. Proteomic analysis revealed substantial remodeling in both aged and Sirt1⁺/^- testes, with overlapping alterations affecting proteins involved in oxidative stress responses, proteostasis, and chromatin regulation. Moreover, several proteins with recognized anti-aging functions were undetectable in both aged and Sirt1⁺/^- models yet consistently expressed in wild-type testes. This deregulation reinforces the notion that testicular SIRT1 insufficiency recapitulates key features of the aging testis.

Our findings indicate that partial loss of SIRT1 is sufficient to trigger proteomic and functional hallmarks of testicular aging. In particular, we identified specific proteomic signatures linked to subfertility, including the loss of key capacitation-related proteins regulated by SIRT1 in the testis, a pattern also observed in aged animals, which may represent a mechanistic model of SIRT1-governed fertilization failure.